Ring-Expanding Reaction of Cyclopropyl Amides with Triphenylphosphine and Carbon Tetrahalide
SCHEME 1
Yong-Hua Yang and Min Shi* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
[email protected] Received August 10, 2005
We succeeded in activating cyclopropyl amides (monoactivated cyclopropane) through the corresponding imidoyl halides prepared in situ in the presence of 2 equiv of PPh3 and 1 equiv of CX4, and the ring-expanding products (Nsubstituted pyrrolidin-2-ones) were obtained in good yields. The reaction mechanism was investigated on the basis of oxygen-18 tracer experiment.
Cyclopropane derivatives as versatile building blocks have been more than laboratory curiosities for quite some time.1 To activate strained three-membered ring, electrondonating or -accepting substituents are generally involved in their reactions to make polar processes more favorable. However, cyclopropane-involved synthetically useful reactions frequently contain two activating groups.2 The ring-opening reactions of monoactivated cyclopropane derivatives are in general sluggish due to their low reactivities. So far, several examples have been reported under severe conditions either treated with stronger nucleophiles such as I- 3 and stronger Lewis acids such as TiCl44 or assisted by the β-effect of the silicon atom of trimethylsilyl group.5 Therefore, it is necessary to develop a method for the ring-opening reaction of simple monoactivated cyclopropane derivatives under mild conditions. (1) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b) Paquette, L. A. Chem. Rev. 1986, 86, 733. (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (d) de Meijere, A.; Wessjohann, L. Synlett 1990, 20. (e) Kulinkovich, O. G. Russ. Chem. Rev. 1993, 62, 839. (f) Kulinkovich, O. G. Polish J. Chem. 1997, 849. (g) Wenkert, E. Acc. Chem. Res. 1980, 13, 27. (h) Wenkert, E. Heterocycles 1980, 14, 1703. (i) Seebach, D. Angew. Chem. 1979, 91, 259; Angew. Chem. Int. Ed. Engl. 1979, 18, 239. (j) Reiser, O. Chem. Rev. 2003, 103, 1603. (2) 2 (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66. (b) Avilov, D. V.; Malusare, M. G.; Arslancan, E.; Dittmer, D. C. Org. Lett. 2004, 6, 2225. (3) (a) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 987. (b) Truce, W. E.; Lindy, L. B. J. Org. Chem. 1961, 27, 1463. (c) Smith, A. B., III; Scarborough, R. M. Tetrahedron Lett. 1978, 19, 1649. (d) Ogoshi, H.; Kikuchi, Y.; Yamaguchi, T.; Toi, H.; Aoyama, Y. Organometallics 1987, 6, 2175. (e) Hwu, J. R. Chem. Commun. 1985, 452. (f) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147. (g) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 4333.
Triphenylphosphine with carbon tetrachloride or carbon tetrabromide has been found widespread use as a reagent for the conversion of alcohols, acids, and amide derivatives into the corresponding halides, nitriles, and carbo imide derivatives.6 Ziehn and co-workers also described the preparation of imidoyl halides (chlorides and bromides) through simultaneous treatment of the monosubstituted amides with triphenylphosphine and carbon tetrahalide (CX4, X ) Cl and Br) in acetonitrile.7 On the basis of this result, we suppose that if cyclopropyl amides 1 can be converted into the corresponding imidoyl halide derivatives 2, their reactivities would be increased because there exist two electron-withdrawing groups in their structures (CdN and C-X) (Scheme 1). To determine whether this speculation is possible, we attempted the reaction of cyclopropyl amides 1 with PPh3/ CX4 under similar conditions. As an initial examination, we found that the reaction of N-phenylcyclopropylamide 1a with 2 equiv of Ph3P and 1 equiv of CCl4 produced the N-phenylpyrrolidin-2-one 3a in 62% yield under reflux for 3 days in acetonitrile (Table SI-1, Supporting Information, entry 1). When we utilized CBr4 instead of CCl4, this reaction proceeded smoothly at 60 °C under similar conditions to give 3a in 97% yield after 3 h. After optimization of the reaction conditions (Table SI-1, Supporting Information), we found that 2 equiv of Ph3P and 1 equiv of CBr4 are required in this reaction to give 3a in good yield and acetonitrile is the best solvent, which is similar to those of other reaction systems using triphenylphosphine and carbon tetrahalide as reagents.6,8 It should be emphasized here that we also attempted to activate cyclopropylamide 1a with PCl59 and POCl3, respectively,10 typical VilsmeierHaack reaction conditions, but the desired product 3a was not formed. At the present stage, we only found that the reagent of PPh3/CBr4 can effectively promote this ring-expanding reaction. It is well-known that lactam rings are important structures in a number of biologically and pharmaceuti(4) (a) Lim, Y.-H.; McGee, K. F., Jr.; Sieburth, S. M. J. Org. Chem. 2002, 67, 6535. (b) Yates, P.; Helferty, P. H.; Mahier, P. Can. J. Chem. 1983, 61, 78. (c) Demuth, M.; Raghavan, P. R. Helv. Chim. Acta 1979, 62, 2338. (5) Yadav, V. K.; Balamurugan, R. Org. Lett. 2003, 5, 4281. (6) (a) Rabinowitz, R.; Marcus, R. J. Am. Chem. Soc. 1962, 84, 1312. (b) Ramirez, F.; Desai, N. B.; Mckelvie, N. J. Am. Chem. Soc. 1962, 84, 1745. (c) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley-Interscience New York, 1972; Vol. 3, p 320. (d) Gadogan, J. I. G.; Mackie, R. K. Chem. Soc. Rev. 1974, 3, 87. (7) (a) Appel, R.; Warning, K.; Ziehn, K.-D. Chem. Ber. 1973, 106, 3450. (b) Appel, R.; Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (c) Zhong, Y.-L.; Lee, J.; Reamer, R. A.; Askin, D. Org. Lett. 2004, 6, 923. (8) (a) To¨mo¨sko¨zi, I.; Gruber, L.; Radics, L. Tetrahedron Lett. 1975, 16, 2473. (b) Aneja, R.; Davies, A. P.; Knaggs, J. A. Tetrahedron Lett. 1974, 15, 67. (9) Langer, P.; Helmholz, F.; Schroeder, R. Synlett. 2003, 2389. (10) Herbert, J. M.; Woodgate, P. D.; Denny, W. A. J. Med. Chem. 1987, 30, 2081.
10.1021/jo0516988 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/15/2005
J. Org. Chem. 2005, 70, 8645-8648
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TABLE 1. Reaction of Various N-Substituted Cyclopropyl Amides with PPh3 and CBr4 in Acetonitrile
a Isolated yields. b The structure was determined by X-ray diffraction (see the Supporting Information). c The yield was determined by 1H NMR spectroscopic data.
cally active compounds as well as some alkaloids such as cotinine or mannolactam.11 Among these lactam compounds, pyrrolidinones are often found in a variety of pharmacologically active compounds, for example, convultamides,12 enzyme inhibitors,13 and various drugs.14 Therefore, to extend the scope of this interesting ringexpanding reaction, we next carried out the reactions of a variety of N-substituted cyclopropylamides 1 in the presence of PPh3/CBr4 under the optimized reaction conditions. In all of the cases we examined, the corresponding ring-expanding products (N-substituted pyrrolidin-2-ones) 3 were exclusively formed in 58-97% yields. The results are summarized in Table 1. For both aromatic cyclopropylamides and aliphatic cyclopropylamides, the reactions proceeded smoothly to give the desired products 3 in good to high yields. More importantly, for sterically hindered ortho-substituted cyclopropyl amide 1f, this reaction also proceeded smoothly to give the corresponding pyrrolidin-2-one product 3f in 86% yield (Table 1, entry 6). For cyclopropyl amide 1k (R2 ) phenyl group), the reaction became sluggish and the corresponding ringexpanding product 3k was only obtained in 26% yield even if the reaction time was prolonged to 1 day, and in the meantime, decomposition of starting material was also observed (Table 1, entry 11). It should be noted that the ester group is tolerable under the reaction conditions (11) (a) Milewska, M. J.; Bytner, T.; Połon˜ski, T. Synthesis 1996, 1485. (b) Neurath, G. B. In Nicotine Related Alkaloids; Gorrod, J. W., Ed.; Chapman: London, 1993; p 61. (c) Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59, 3575. (12) Zhang, M.; Shigemori, H.; Ishibashi, M.; Kosaka, T.; Pettit, G. R.; Konano, Y.; Kobayashi, J. Tetrahedron 1994, 50, 10201. (13) Baures, P. W.; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L. B.; Torphy, T. J.; Christensen, S. B. J. Med. Chem. 1993, 36, 3274. (14) Marson, C. M.; Grabowska, U.; Walsgrove, T.; Eggleston, D. S.; Baures, P. W. J. Org. Chem. 1994, 59, 284.
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(Table 1, entry 7). Moreover, these reactions can be carried out under ambient atmosphere. Interestingly, when N,N′-bis(cyclopropylcarbonyl)benzidine 4 was utilized as a substrate, the corresponding ring-expanding product 5 can also be obtained in 86% yield (Scheme 2). However, when N,N′-bis(cyclopropylcarbonyl)[1,1′]binaphthalenyl-2,2′-diamine 6 (racemate) was employed as a substrate, the ring-opened product 7 was exclusively obtained. We believe that the significant steric hindrance in this substrate hampered the ringexpanding reaction. Moreover, this result mechanistically suggests that the ring-opened product, 4-bromobutyramide, may be a key intermediate in this reaction. Therefore, to clarify the mechanism of this reaction, we treated 4-bromo-N-phenylbutyramide 8 under the same conditions with PPh3 and CBr4 at 60 °C in acetonitrile and found that the corresponding pyrrolidin-2-one 3a, as expected, was formed in 94% yield after 10 h (Scheme 3). On the other hand, the control experiments showed that treatment of 1a with base such as NaOEt, Brønsted acid such as hydrobromic acid (HBr), or Lewis acid TiX4 containing halogen ions (X ) Cl or Br) did not promote this reaction under similar conditions. These results again indicated that the combination of PPh3 and CBr4 is the only useful reagents for this reaction. To further clarify the mechanism of this reaction, we carried out the reaction of 1a with PPh3/CBr4 in the presence of 18OH2.15 As a result, we found that 3a-18O was formed in 88% yield with 59.2% 18O content in the oxygen atom of carbonyl group, which was determined by magnetic mass spectroscopic analysis (see Scheme SI4, Supporting Information). This result clearly indicates that the oxygen atom of the carbonyl group in lactam product 3 comes from H2O in the reaction system and the original oxygen atom in 1a is taken away by Ph3P as Ph3PO. After examination of the resulted byproducts, we confirmed that Ph3PO was indeed formed in this reaction system. In view of the above results, a plausible reaction mechanism is proposed in Scheme 4. At first, triphenylphosphine reacts with carbon tetrahalide to give the corresponding dihalogentriphenylphosphorane 9 and dihalogenmethylene ylide 10. Next, the intermediate A is formed by the reaction of N-substituted cyclopropylamide 1 with dihalogentriphenylphosphorane 9 to release a dihalogenmethyltriphenylphosphonium salt 11 as white precipitates, which was dissolved in MeCN after the solution was heated to 60 °C.8 Thus, the corresponding N-substituted cyclopropylformimidoyl halogen B, as an anticipated active iminocyclopropane intermediate having two electron-withdrawing groups, is formed along with the generation of triphenylphosphine oxide. From intermediate B, two reaction pathways can be considered for the formation of pyrrolidin-2-one product 3. Formally, the intermediate C can be first formed via a Cloke-type rearrangement from intermediate B. The corresponding pyrrolidin-2-one product 3 is formed through water substituting X by OH (Scheme 4, path a). However, it has been reported that typical Cloke rearrangement normally proceeds from an imine by acid catalysis at (15) H2O (1.0 equiv) must be added slowly to the reaction mixture of 1a with PPh3/CBr4 in MeCN at 60 °C; otherwise, the yield of 3a would be decreased.
SCHEME 2. Ring-Expanding Reaction of 4 and Ring-Opening Reaction of 6 with PPh3/CBr4
SCHEME 3. Ring-Closure Reaction of 4-Bromo-N-phenylbutyramide 8 with PPh3 and CBr4
SCHEME 4. Plausible Reaction Mechanism of the Ring-Expanding Reaction of Cyclopropyl Amide in the Presence of PPh3 and CX4
I- could promote Cloke-type rearrangement through a ring-opening process under milder reaction conditions (85-90 °C).17 Therefore, on the basis of above results, we believe that ring-opening reaction of intermediate B, having two electron-withdrawing groups, takes place by the nucleophilic attack of X- in dihalogen methyltriphenylphosphonium salt 11 to give another cyclopropylformimidoyl halogen intermediate D which is labile toward ambient H2O in any sense.18 In the presence of ambient moisture (H2O), 4-halobutyrimidic acid intermediate E is formed through water substituting X by OH which is in an equilibrium with 4-halobutyramide F (Scheme 4, path b). The intramolecular nucleophilic attack produces the corresponding ring-closure product 3 by release of a HX (path b). If the ring-closure process is difficult to take place because of the steric hindrance, the corresponding 4-halobutyramide F will be obtained. The control experiment has showed that 4-halobutyramide F, which has been isolated from a steric hindered cyclopropyl amide in Scheme 2, can be transformed to product 3 under the reaction conditions (Scheme 3). In conclusion, treatment of cyclopropyl amides with 2 equiv of PPh3 and 1 equiv of CX4 (X ) Cl, Br) produce the corresponding N-substituted pyrrolidin-2-one 3 in good to high yields via imidoyl halides intermediate. On the basis of oxygen-18 labeled experimenst, we clarified that the oxygen atom of the obtained lactam arises from participation of adventitious H2O in the reaction system and a plausible reaction mechanism was proposed. Continuing efforts are in progress to disclose the mechanistic details of this reaction and to determine its scope and limitations. Experimental Section General Methods. Melting points are uncorrected. 1H and NMR spectra were recorded at 300 and 75 MHz, respectively. Mass and HRMS spectra were recorded by EI methods. Organic solvents used were dried by standard methods when necessary. Commercially obtained reagents were used without further purification. All reactions were monitored by TLC with silica gel coated plates. Flash column chromatography was carried out using silica gel at increased pressure. General Procedure for the Reactions of Cyclopropanecarbonyl Amide with PPh3 and CBr4. A mixture of cyclopropanecarbonyl amide (0.3 mmol), PPh3 (197 mg, 0.75 mmol), and CBr4 (100 mg, 0.3 mmol) was dissolved in acetonitrile (3 13C
elevated temperatures, typically by heating the substrate as a melt, or in xylene with ammonium chloride at >130 °C.16 Moreover, Giller and co-workers also reported that (16) Cloke, J. B. J. Am. Chem. Soc. 1929, 51, 1174. (b) Stevene, R. V.; Ellis, M. C.; Wentland, M. P. J. Am. Chem. Soc. 1968, 90, 5576. (c) Stevene, R. V.; Wentland, M. P. J. Am. Chem. Soc. 1968, 90, 5580. (d) Stevene, R. V.; Luh, Y.; Sheu, J.-T. Tetrahedron Lett. 1976, 3799. (17) Giller, K.; Baird, M. S.; de Meijere, A. Synlett 1992, 524. (18) The hydroscopic tendency of imidoyl halides has been mentioned in many papers: (a) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama, K. J. Org. Chem. 1993, 58, 32. (b) Ghosez, L.; Haveaux, B.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1969, 8, 454. (c) Sidani, A.; Marchand-Brynaert, J.; Ghosez, L. Angew. Chem., Int. Ed. Engl.
1974, 13, 267. (d) Marchand-Brynaert, J.; Ghosez, L. J. Am. Chem. Soc. 1972, 94, 2870. (e) Ghosez, L. Angew. Chem., Int. Ed. Engl. 1972, 12, 852. (f) Harvill, E. K.; Herbst, R. M.; Screiner, E. C.; Boberts, C. W. J. Org. Chem. 1950, 58, 662. (g) Uneyama, K.; Kobayashi, M. Tetrahedron Lett. 1991, 32, 5981.
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mL). A short time later, a white precipitate was formed from the reaction solution. Then, the reaction system was heated to 60 °C, and the precipitate was dissolved again in the reaction solution. The solvent was evaporated after all starting amides were consumed. The residue was dissolved in CH2Cl2 (50 mL) and washed with H2O (50 mL × 2). After the residue was dried over anhydrous MgSO4, the solvent was removed under reduced pressure and the residue was purified by a silica gel column chromatography to give pyrrolidin-2-one product. 1-Phenylpyrrolidin-2-one 3a. This compound was obtained as a white solid. Yield: 47 mg, 97%. Mp: 64-65 °C. IR (CH2Cl2): ν 1120, 1226, 1301, 1396, 1459, 1500, 1597, 1684, 2930, 2986 cm-1. 1H NMR (300 MHz, CDCl3, TMS): δ 2.12 (tt, J ) 8.1 Hz, J ) 7.2 Hz, 2H, CH2), 2.58 (t, J ) 8.1 Hz, 2H, CH2), 3.82 (t, J ) 7.2 Hz, 2H, CH2), 7.10-7.15 (m, 1H, Ar), 7.32-7.38 (m,
2H, Ar), 7.57-7.61 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3, TMS): δ 18.0, 32.7, 48.8, 119.9, 124.5, 128.8, 139.4, 174.2. MS (EI) m/z: 161 (M+, 42), 132 (3), 119 (3), 106 (100), 104 (11), 91 (5), 79 (6), 77 (28), 51 (15). HRMS (MALDI) calcd for (C10H12NO + H)+ 162.0913, found 162.0913.
(19) The crystal data of 3c have been deposited at the CCDC, no. 264862: empirical formula, C12H15NO3; formula weight, 221.25; crystal size, 0.508 × 0.249 × 0.214; crystal color, habit, colorless, prismatic; crystal system, triclinic; lattice type, primitive; lattice parameters, a ) 8.4864(11) Å, b ) 8.5841(11) Å, c ) 8.6437(12) Å, R ) 98.452(2)°, β ) 101.450(2)°, γ ) 114.134(2)°, V ) 544.40(12) Å3; space group, P-1; Z ) 8; Dcalc ) 1.350 g/cm3; F000 ) 236; R1 ) 0.0579, wR2 ) 0.1479. Diffractometer: Rigaku AFC7R.
Supporting Information Available: The spectroscopic data, the detailed description of experimental procedures, the mass spectroscopy of 18O-labeled N-phenylpyrrolidin-2-one 3a, and the X-ray crystal data of 3c.19 This material is available free of charge via the Internet at http://pubs.acs.org.
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Acknowledgment. We thank Dr. Hao-Yang Wang and Guo-Qing Dong for mass spectrometry assistance. We also thank the State Key Project of Basic Research (Project 973) (No. G2000048007), Shanghai Municipal Committee of Science and Technology, and the National Natural Science Foundation of China for financial support (20025206, 203900502, and 20272069).
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